There are currently no effective strategies for the treatment of chronic airway fibrosis in asthma or interstitial pulmonary fibrosis that result from environmental exposures to a wide variety of inhaled allergens and toxicants. It is generally accepted that current anti-inflammatory therapies fail to improve fibrotic outcomes in the lung. Therefore, the development of translational approaches that target fibrosis are urgently needed. Our work has shown that interleukin (IL)-13, a key mediator of asthma and fibrosis, stimulates the production of platelet-derived growth factor (PDGF). The binding of PDGF to cell-surface PDGF receptors results in the proliferation of fibroblasts, the principal cell type that secretes collagen to form fibrotic scar tissue. IL-13-induced PDGF production by lung cells is tightly regulated by STAT transcription factors; STAT-6 promotes IL-13-induced PDGF production while STAT-1 suppresses PDGF production. The primary objective of this project is to explore innovative strategies aimed at reducing IL-13-induced PDGF signaling and fibrosis. Our hypothesis is that inhibition of PDGF production, PDGF receptor binding, or PDGF receptor phosphorylation will reduce airway or interstitial fibrosis in established mouse models of chronic lung disease. In the first aim we will determine whether the oral administration of bis(maltolato)oxovanadium(IV) (BMOV), a bioavailable form of vanadium that is used for diabetes therapy, decreases PDGF levels and airway fibrosis in vivo in mouse models of asthma and interstitial pulmonary fibrosis. Because vanadium activates STAT-1 to reduce IL-13-induced PDGF production in lung cells in vitro, we will determine if BMOV reduces airway fibrosis in vivo using the ovalbumin mouse model of asthma and in a bleomycin mouse model of interstitial fibrosis. In the second aim we will determine whether administration of a monoclonal neutralizing antibody to selectively block PDGF binding to the PDGF receptor reduces fibrosis in mouse models of asthma and pulmonary fibrosis. In the final aim, we will determine whether blocking PDGF receptor tyrosine kinase activity reduces fibrosis in a mouse model of asthma. This aim will utilize the receptor tyrosine kinase inhibitor, imatinib mesylate, to block PDGFR phosphorylation. If any one of the three proposed strategies for blocking PDGF signaling result in amelioration of fibrosis, then this would provide a breakthrough for future application to clinical trials aimed at the treatment of airway fibrosis in asthma or interstitial pulmonary fibrosis. Asthma and pulmonary fibrosis are chronic lung diseases that result from environmental exposure and genetic susceptibility to a wide variety of inhaled allergens and toxicants. In the United States there are over 200,000 patients with pulmonary fibrosis, and of these over 40,000 expire annually. 20 million people in the United States have been diagnosed with asthma and nearly 9 million of them are children. Therefore, these chronic lung diseases clearly pose a major health problem. Airway fibrosis in asthma is part of a chronic remodeling process that contributes to the obstructive nature of this disease and reduces lung function. Moreover, there are currently no effective treatment strategies to reduce airway fibrosis in chronic asthma, nor are drugs available that significantly reduce interstitial pulmonary fibrosis. We will attempt to develop preclinical strategies aimed at reducing growth factor signaling, fibroblast proliferation, and collagen deposition in mouse models of chronic asthma and interstitial pulmonary fibrosis. [unreadable] [unreadable] [unreadable]